The present invention provides a new use of known compositions. More particularly, the present invention provides a method for the prevention of venous thrombosis using lipoxygenase inhibitors.
Thrombosis of the lower limb deep veins, or deep vein thrombosis (DVT) is a frequent occurrence after major surgery, massive trauma, myocardial infarction, neoplasia, and pregnancy. (See, e.g., Bell, et al., Am. Heart J. 103: 239 (1982), Coon, Ann. Surg. 186: 149 (1977), and Kakkar, et al., Am. J. Surg. 120: 527 (1972).) While DVT may not always be dangerous, growth of thrombi and their subsequent embolization may become life threatening if these emboli lodge in the pulmonary circulation. It has been estimated that 11-20% of all venous thrombi will embolize. (See, Freeman, et al., N. Engl. J. Med. 272: 1270 (1965) and Salzman, et al., Am. Surg. 93: 207 (1980).) Therapeutic interventions for prevention of venous thrombosis, while available, have not been demonstrated to be completely effective or without significant side effects in the high risk patient. Low dose heparin is effective in the prevention of DVT in the general surgical patient. However, low dose heparin appears to be without significant effect in the prevention of DVT in patients in orthopedic surgical procedures, in trauma cases, following colorectal surgery, and in post myocardial infarct patients. See, e.g., Bell, supra, Freeman, supra, Gallus, et al., N. Engl. J. Med. 288: 454 (1973), Kass, et al., J. Urol. 120: 239 (1982), Salzman, et al., N. Engl. J. Med. 284: 287 (1971), and French, et al., The Lancet, 1 (8231): 1212 (1981). Warfarin when given prophylactically can significantly reduce DVT in highest risk patients, but bleeding is a frequent complication of oral anti-coagulation (see, Salzman, Am. Surg. 93: 207 (1980)). Fatal hemorrhage has been reported in 1.8 percent of the patients on Warfarin. See, Gallus, et al., Thromb. Hemostasis (2: 291 (1976). Low molecular weight dextran therapy for DVT is complicated by the possibility of anaphylaxis, pulmonary edema subsequent to volume overload, and renal damage. See, Bell, supra and Salzman, supra. Aspirin has proved effective in high risk male patients but not in high risk female patients. See, Salzman, supra at Harris, et al., N. Engl. J. Med. 297: 1246 (1977).
In mammalian metabolism, arachidonic acid is transformed to 12-L-hydroproxy-5,8,10,24-eicosatetraenoic acid by the action of 14-lipoxy-genase. See, Hamberg, et al., Proc. Nat. Acad. Sci. 71: 3400-3404. Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6-8,11,14-eicosatetraenoic acid. Doig, et al., Prostaglandins: 1007-1009 (1980) and Lynn, et al., J. Clin. Invest. 70: 1058 (1982) disclosed that 5-lipoxygenase inhibitors block platelet thrombus formation.
It has been suggested that leukocytes contribute to the initiation of venous thrombosis by producing endothelial damage. See, e.g., Stewart, et al., Am. J. Path. 75: 507 (1974). Arachidonic acid, when metabolized by lipoxygenase produces mono-, di-, and trihydroxyeicosatetraenoic acids (HETE's). Recent evidence indicates that the substances (leukotrienes) are important mediators of the inflammatory process, stimulating the chemoattraction of leukocytes and their adhesion to the vascular endothelium. See Agges, et al., Biochem. Pharmacol. 28: 1959 (1979), and Sammuelsson, et al., Ann. Rev. 47: 997 (1978). The compound 5-12-di-HETE (leukotriene B.sub.4) is a very potent activator. See, Ford-Hutchinson, et al., Nature 286: 264 (1980). Two other leukotrienes, leukotrienes C.sub.4 and D.sub.4 also appear to have a role in the chemotactic response. Both of these substances have been found to induce vasoconstriction and to increase vascular permeability. See, Peck, et al., Prostaglandins 21: 315 (1981).
Certain inhibitors of lipoxygenase are known. Thus, Hammarstrom, Biochim. Biophys. Acta. 487: 517 (1977) discloses the lipoxygenase inhibitory activity of 5,8,11-eicosatriynoic acid. Vanderhoek, et al., J. Biol. Chem. 255: 5996 (1980) discloses 15-hydroxy-5,8,11,13-eicosatetraenoic acid as a selective inhibitor of platelet lipoxygenase. Seckiya, et al., Biophys, Res. Comm. 105: 1090 (1982) reports that baicalein is a selective inhibitor of platelet lipoxygenase, while Bokoch, et al., J. Biol. Chem. 256: 5317 (1981) states that nordihydroguaiaretic acid (NDGA) is also a lipoxygenase inhibitor. Certain quinone compounds are disclosed as lipoxygenase inhibitors in U.S. Pat. No. 4,393,075.